1-(beta-aminoethyl)-4-(beta-hydroxyethyl)-piperazine



United States Patent Set. No. 153,745

1 Claim. 01. 260-268) The novel compounds of this invention may beprepared by reacting the corresponding halogen precursor compounds withanhydrous ammonia, or by the hydrogenation of the corresponding cyanoprecursor compounds, as more fully is shown in the examples set forthhereinafter.

Our novel heterocyclic amines are useful as intermediates for thepreparation of thiaxanthenone derivatives in accordance with theprocedure set forth in the examples which follow.

The thiaxanthenone derivatives formed from the novel heterocyclic aminesof this invention'are useful as chemotherapeutic agents for treatingschistosorniasis. They are preferably employed for this purpose in theform of hydrohalides, especially the hydrochlorides. These materials canbe administered in the form, dosage and manner as the antischistosomeagent, 1-methyl-4-B-diethylaminoethylamino-thiaxanthenone hydrochloride(Miracil D), is administered.

The invention is further illustrated by the following examples, in whichall temperatures, unless otherwise indicated, are in degrees centigrade.

EXAMPLE I In this example, N-ethyl-Z arninoethylpiperidine ispreparedfrom N-ethyl-Lchlorornethylpiperidine hydrochloride, which is made fromN-ethyl-2-hydroxymethylpiperidine, which is obtained, alternatively,from Z-acetoxy methylpyridine or 2-hydroxymethylpyridine. 1-(2-N-ethylpiperidylmethylamino) 4 methyl-l0-thiaxanthenone hydrochloride isthen prepared from 'N-ethyl-2- aminoethylpiperidine.

N-Ethyl-Z-Hydroxym ethylpiperidine (A) FROM '2ACETOXYMETHYLPYRIDINE Asolution of 117 g. of Z-acetoxymethylpyridine, prepared frompicoline-N-oxide, in 300 ml. of ethanol was shaken under hydrogen atl900 =p.s.i. at 19 for 20 hours, in the presence of g. of 10% rutheniumon carbon. The solution was filtered and concentrated under reducedpressure to ca. 200 ml. After the addition of 100 ml. of aceticanhydride the solution was again concentrated under reduced pressure toca. 200 ml., and was stored at room temperature for 18 hours.Fractionation of the reaction mixture through a 8" Vigreux columnafforded 23.6 g. of N-acetyl-2-acetoxy-methylpiperidine, B.P. 135 (0.8mm.), n 1.4850.

Analysis.Calcd. for C H O N: C, 60.26; H, 8.62; N, 7.06. Found: C,60.36; H, 8.35; N, 6.98.

To a suspension of 8 -g. of lithium aluminum hydride in 800 ml. oftetrahydrofuran was added slowly with icecooling and stirring a solutionof 19.9 g. of N-acetyl-2- a-cetoxymethylpiperidine in 40 ml. oftetrahydrofuran. The mixture was stirred at 0 for 0.5 hr., atroomtemperature for 2 hours, and was then heated at the refluxtemperature for 2 hrs. After the addition of ethyl acetate and 20 ml. ofice-water with cooling, the supernatent solution was decanted. The solidresidue was dissolved in dilute sodium hydroxide and extracted con- "icetinuously with ether for 24 hrs. The ethereal extract was combined withthe tetrahydrofuran solution, 'dried over potassium carbonate, filtered,concentrated, and fractionated. N-ethyl-2=hydroxymethylpiperidine (8.6g.) was collected at B.P. 102 (16 mm), n 1.4834.

Analysis.Calcd. for C H NO: C, 67.08; H, 11.97. Found: C, 67.16; H,11.62.

(B) FROM 2-HYDROXYMETHYLPYRIDINE A solution of 250 g. of2-hydroxymethylpyridine in 450 ml. of ethanol was hydrogenated at100-125 under 4200 p.s.i. in the presence of a Raney nickel catalyst.The solution was filtered and treated with 250 g. of ethyl bromide and180 g. of potassium carbonate at room temperature for 3.5 days withoccasional shaking. The reaction mixture was filtered, concentratedunder reduced pressure to a syrup and filtered again. The solid wasdissolved in 200 ml. of water, saturated with potassium carbonate andextracted with chloroform. The chloroform extract was combined with thesyrup and distilled to afford 223 g. (68%) ofN-ethyl-2-hydroxymethylpiperi-dine.

N-Ethyl-2-Chloromethylpiperidine Hydrochloride A solution of g. ofN-ethyI-Z-hydroxyrnethylpiperidine in 500 ml. of chloroform was treatedwith excess hydrogen chloride with ice-cooling. Thionyl chloride g.) wasadded slowly with stirring and ice-cooling and the mixture was stirredat room temperature for 1 hr. followed by heating at the refiuxtemperature for 1 hr. The solution was evaporated under reduced pressureto a semi-solid which was recrystallized from ethanolethyl acetate aswhite needles, M.P. 197. was 64 g.

AnaIysis.-Calcd. for CgH NCl C, 48.5; H, 8.67. Found: C, 48.91; H, 8.70.

N-Ethyl-Z-Aminomethylpiperidine The yield 1(Z-N-Ethylpiperidylmethylamino) -4-Methyl-10- Thiaocanthenone Hydrochloride A mixture of 40g. of isomeric chlor-omethylthiaxanthenone, 30 g. ofN-ethyl-Z-aminomethylpiperidine and 20 ml. of pyridine was heated at thereflux temperature for 16 hrs. The reaction mixture was treated withexcess of dilute sodium carbonate, and the precipitate was collected anddigested with acetic acid. After dilution with 3 volumes of water theacetic acid solution was filtered, and was then neutralized withammonium hydroxide. The free base separated was collected, dissolved inethanol and treated with ethanolic hydrogen chloride. The salt wasrecrystallized from ethanol, M.P. 218 (9.5 g.).

Analysis.-Calcd. for C H N OSCl: C, 65.7; H, 6.72; N, 6.97. Found C,66.11; H, 6.57; N, 674.

EXAMPLE II In this example, 1-(B-aminoethyl)-4-(;3-hydroxyethyl)-piperazine was derived from 1-cyanomethyl-4-{3-hydroxyethylpiperazine,which was derived in two ways, first from 1-,B-hydroxyethylpiperazine byconversion of the latter to a crystalline sodium sulfonate which wasthen treated with potassium cyanide, and second by alkylation of 1-5-hydroxyethylpiperazine with chloroacetonitrile. 1-(}3-4'-hydroxyethylpiperazineylethylamino) 4 methyHO-thiaxanthenonedihydrochloride was then prepared from the above heterocyclic amine.

1-Cyan0methyl-4-,8-Hydroxyethylpiperazine (A) FROM CRYSTALLINE SODIUMSULFONATE A solution of 0.18 mole of sodium bisulfite and 0.18 mole offormaldehyde in 35 ml. of water was mixed with g. of1qs-hydroxyethylpiperazine with stirring and cooling. The whiteprecipitate formed was collected on a filter, washed with ethanol anddried. The product was redissolved in ml. of water. After the additionof 12 g. of potassium cyanide, the mixture was heated on a steam bathwith occasional shaking for one hr. Excess of potassium carbonate wasadded, and the product was extracted with chloroform. Evaporation of thechloroterm solution gave a brown syrup, and this was again extractedwith three portions of 150 ml. of ether leaving a solid residue, M.P.80. The ethereal solution was concentrated and the product was distilledat B.P. 113114 (0.2 mm.), 11 1.5062. The oil crystallized on coolingM.P. 40. The yield was 16.3 g (63%) Analysis.Calcd. for C H N O: C,56.8; H, 8.88; N, 24.9. Found: C, 56.19; H, 8.51; N, 25.07.

The product formed a dihydrochloride, which was recrystallized from amixture of methanol and ethanol, M.P. 201 (dec.).

Analysis.Calcd. for C H N OCl: C, 39.7; H, 7.02; N, 17.35. Found: C,39.87; H, 6.89; N, 16.86.

The product was further characterized as its acetate, 1-cyanomethyl-4-fi-acetoxyethylpiperazine, B.P. 120 (0.1 mm.).

Analysis.-Calcd. for C H N O C, 56.9; H, 8.12; N, 19.92. Found: C,56.93; H, 7.67; N, 19.40.

The ether-insoluble residue, M.P. 80, was recrystallized from a mixtureof benzene and chloroform to afiord an analytical pure sample, MP. 9293.This by-product was identified as 1-carbamylmethyl-4-5-hydroxyethy1-piperazine.

Analysis.-Calcd. for C H N O C, 51.3; H, 9.1. Found: C, 51.36; H, 8.27.

The amide was acetylated with acetic anhydride to form 1carhamylmethyl-4-13-acetoxyethylpiperazine, recrystallized from benzenepet. ether, M.P. 81.

Analysis.-Calcd. for C H N O C, 52.45; H, 8.3; N, 18.3. Found: C, 52.79;H, 8.00; N, 17.92.

(B) BY ALKYLATION A mixture of 12 g. of 1-,8-hydroxymethylpiperazine and8 g. of chloroacetonitrile was heated in 200 ml. of ethanol at thereflux temperature for 18 hrs. The solution was evaporated to a syrupunder reduced pressure, and the syrup was redissolved in chloroform. Thesolution was washed with 10% sodium hydroxide solution and dried overpotassium carbonate. Evaporation of the chloroform solution gave a syrupwhich was extracted with three portions of ml. of ether. The etherealsolution was evaporated and fractionated to give the product, B.P. 114(0.2 mm.), which crystallized on cooling, M.P. 3940 (7.4 g.)

A solution of 11 g. of 1-cyanomethyl-4-fl-hydroxyethylpiperazine in 35ml. of ethanol and 25 g. of anhydrous ammonia was hydrogenated in thepresence of one teaspoonful of Raney nickel catalyst under 1700 p.s.i.at 100 for 6 hrs. The solution was filtered and concentrated underreduced pressure. The residual syrup was distilled in a short-pathdistillation apparatus with a bath temp. of 200 (1 mm.) to afiord 10.1g. of the product, 11 1.5140.

The product formed a trihydrochloride which was recrystallized fromaqueous ethanol, M.P. 241-243".

AnalysisCalcd. for C H N OCl C, 34.1; H, 7.8; N, 14.85. Found: C, 34.58;H, 7.49; N, 15.16.

1- (fl-4-Hydr0xyethylpiperazinylethylamino) -4-Methyl- JO-ThiaxanthenoneDihydrochloride A mixture of 3 g. of1-fi-aminoethyl-4-fl-hydroxyethylpiperazine and 5 g. of isomericchloromethylthiaxanthenones was heated in 5 ml. of pyridine at thereflux temp. for 22 hrs. The solution was poured into dilute sodiumhydroxide and the precipitate was collected and digested with 50 ml. of20% acetic acid containing 2 ml. of hydrochloric acid. The reddishsolution was filtered and neutralized with dilute sodium hydroxide. Theprecipitate formed was collected and washed thoroughly with water. Itwas redissolved in ethanol and the solution was treated with excess ofethanolic hydrogen chloride. The dark red solution was evaporated underreduced pressure, and the residue was recrystallized from aqueousethanol as yellow needles, M.P. 238240 (1.1 g.).

Analysis.Calcd. for C22H29N302SC12Z C, H, 6.23; N, 8.94. Found: C,56.02; H, 6.18; N, 8.92.

The present application is a division of our copending application,Serial No. 767,102, filed October 14, 1958, now Patent No. 3,031,452.

We claim:

1- (fi-aminoethyl -4-(,B-hydroxyethyl -piperazine.

References Cited in the tile of this patent FOREIGN PATENTS

